Are You Confident of the Diagnosis?

What you should be alert for in the history

Most often patients will display a cutaneous livedo vascular pattern with or without underlying systemic symptoms other than mild joint or muscle discomfort in cutaneous polyarteritis nodosa (CPAN). Systemic polyarteritis nodosa (PAN) patients may have fever, malaise, and signs or symptoms similar to other patients with systemic vasculitis. Pulmonary signs or symptoms are not as common in PAN as in the anti-neutrophil cytoplasmanic antibody (ANCA) associated vasculitides.

Characteristic findings on physical examination

These include a cutaneous livedo vascular pattern with or without underlying nodules preferentially on the lower extremities (CPAN) (Figure 1) or in the case of systemic PAN, palpable purpura on the extremities with or without livedo. Ulcerations develop in untreated patients with more severe disease. The upper thighs and buttock are not uncommon locations of involvement and at times the upper extremities may be involved.

Figure 1.

Livedo vascular pattern typical of cutaneous polyarteritis nodosa

Expected results of diagnostic studies

In the case of palpable purpura the cutaneous biopsy will show leukocytoclastic vasculitis. In patients with the livedo and nodules characteristic of CPAN, there will be a single or a few (2 to 4) arterioles involved in the deep dermis and superficial panniculus with transmural inflammation and surrounding mixed pannicular inflammation with lymphocytes and occasionally eosinophils (Figure 2).

Figure 2.

PAN tends to be ANCA negative, at least with regard to the more specific patterns of cytoplasmic-ANCA-proteinase 3 (PR3-C-ANCA) or perinuclear-ANCA-myeloperoxidase (MPO-P-ANCA). PAN patients may be hepatitis B positive but CPAN patients are most often negative for Hepatitis B or C.

Neuropathy is the most commonly seen systemic association with CPAN and most often involves the lower extremities and may cause foot drop or other abnormalities. Peripheral edema is fairly common in CPAN.

Diagnosis confirmation

Diagnosis confirmation requires careful clinical and pathological correlation together with appropriate laboratory work. PAN is a small vessel vasculitis and most often involves a single or a few arterioles, at times affecting the skin. In CPAN most often the capillaries and post-capillary venules as well as the arterioles are involved.

Granuloma formation seen in other ANCA-associated disorders is typically absent. Laboratory tests in CPAN are most often normal or negative except for a modest elevation of the ESR or CRP (5 to 20%) as opposed to the higher elevations seen in PAN or ANCA-associated diseases. Hepatitis serologies are usually negative in CPAN but may be positive in PAN.

Who is at Risk for Developing this Disease?

Similar to other vasculitis syndromes, PAN is uncommon and tends to involve adults in their 30’s to 60’s most often. Women are affected by CPAN more than men.

What is the Cause of the Disease?

Etiology

The etiology is unknown but is thought to represent an autoimmune disease in those who may be susceptible. Active disease may be preceded by infection. Anecdotal cases of CPAN have been reported to occur subsequent to streptococcal infection and with the administration of drugs including minocycline.

Pathophysiology

The pathophysiology is not entirely known. In CPAN patients, an antecedent infection may result in the formation of antibodies, although ANCA does not seem to play a role as of this time. Recent reports have emphasized female preponderance of disease and have raised the possibility of coagulation disorders being involved in the pathogenesis in at least some patients. Local (focal) blood vessel damage in the arteriolar walls followed by clot formation may be at the basis of lesions in CPAN.

Systemic Implications and Complications

Most often CPAN is not associated with other systemic diseases, although a workup for tendencies toward hypercoaguable states have been raised. Hepatitis or liver dysfunction is not often seen in CPAN. Aneurysm formation is not seen in CPAN as it is in PAN. Neuropathy, particulary mononeuritis can be seen in PAN and requires a thorough history and exam and specialty care if identified.

Treatment Options

General principles

The major goal is to relieve pain and achieve healing of the skin lesions, including uclerations. Ulcerative disease tends to be more severe and may be more difficult to heal. Topical care with compresses or dressings for open ulcers may be of help.

Use debridement only if secondary infection is suspected or if the patient is at infection risk due to immune suppression.

In those patients with CPAN and elevated streptococcal antibodies, therapy with penicillin or an alternative should be carried out early on.

Dapsone is an often used option for those with CPAN. Standard precautions should be followed including a screening G6PD test, starting at a lower dose (25 to 50 mg) and frequent CBC testing weekly or every other week until plateau dose is reached. Eventual dose range varies from 50 mg daily to 150 mg daily for adults.

Prednisone is still the most often used drug for those patients with severe symptoms or more severe cutaneous disease including foot drop and mononeuritis. The dose is typically 0.5 to 1.0 mg/kg daily until the skin and symptons improve and then slowly tapered over several weeks.

Azathioprine may be used as a steroid-sparing drug in those patients requiring ongoing therapy or if trials at steroid taper are not successful. The dose is most often 50 to 200 mg daily in adults. Baseline thiopurine methyltransferase (TPMT) is recommended as well as periodic following of CBC and liver function tests.

Mycophenolate mofetil is a good choice for patients requiring additional therapy above prednisone or in those where prednisone cannot be tapered. The dose is most often 500 to 2,500 mg daily in adults.

Methotrexate has been reported to be effective as a steroid sparing agent in some cases but is not used as often as azathioprine. The dose can range from 5 to 25 mg weekly in adults.

Given recent reports of success with combined anti-inflammatory and mild anticoagulant or antiplatelet therapy, consideration should be given to the following list of options depending on the severity of disease and other comorbidities:

Low dose aspirin in those without contraindication may be helpful and continued indefinitely

Pentoxifylline may be used either alone or in combination with aspirin in standard doses

Clopidrogel has been reported to be helpful when used in conjunction with anti-inflammatory therapy

Low molecular weight heparin could be considered in those patients with the severest disease or recalcitrant disease failing more conservative measures above

Hyperbaric oxygen (HBOT) is helpful in cases with refractory ulcers or infection. Most often 20 to 30 treatments are administered at 1.5 to 2.4 atmospheres (ATM).

Optimal Therapeutic Approach for this Disease

Supportive care and relief of pain and discomfort with analgesics and/or topical compresses as required is the first step.

Most patients respond best and fastest to oral prednisone, given in about 0.5 to 1 mg/kg daily doses in adults to start and then tapered very slowly over many weeks to months depending on response and effectiveness.

If an underlying cause such as streptococcal infection is found, treat it and strongly consider prophylaxis therapy.

For patients with milder disease consider dapsone as a steroid sparing agent. Dapsone is a fairly reliable agent for this purpose. For patients with more severe disease, including neuropathic findings and ulceration, add azathioprine or mycophenolate mofetil early on and continue for months or longer to maintain remission.

Consider agents to help prevent clot formation. The simplest regimen could be low dose aspirin and pentoxifylline.

Clopidrogel has been reported to be of help in patients with more severe disease.

Patient Management

Therapy most often includes the use of prednisone in the beginning and until the cutaneous lesions are healed and the patient is mostly free of pain. If streptococcal antibodies are present, treat and then strongly consider prophylaxis going forward. If disorders of coagulations are present, correct them as much as possible. Eliminate any iatrogenic causes for coagulation abnormalities if at all possible. Even in the absence of documented coagulation disorders, it may be of benefit to treat with anti-platelet or mild anticoagulant medications including low dose aspirin, pentoxifylline, or Clopidrogel.

In more severe cases, consideration could be given to use of low molecular weight heparin along with anti-inflammatory therapy. It appears that anti-inflammatory therapy is required in all cases of PAN. If the lesions fail to improve or if remission is not achieved, consider additions to prednisone including mycophenolate mofetil or azathioprine. Dapsone is also a reasonable steroid-sparing drug. Attempt to bring about complete healing before tapering of medications to avoid relapse.

Dapsone, azathioprine and mycophenolate mofetil may be reasonable agents to continue to maintain remission if needed for periods of several months to even years. Relapse in PAN is heralded most often by a return of the pain, including neuropathic pain and nodules and then ulcerations.

CPAN recurrence most often results in skin lesions limited to the lower extremities with occasional extension to the thighs and buttocks. Pain is most often related to the areas of skin lesions including neuropathic symptoms. Extremity edema can also precede skin lesions. Sedimentation rate is usually modestly elevated (less than 40 mm/hr). Systemic symptoms such as fever, extensive joint pain beyond affected extremities, extension of skin lesions, especially nodules and palpable purpura, beyond the lower extremities should prompt re-evaluation for the possibility of systemic vasculitis, including PAN.

Unusual Clinical Scenarios to Consider in Patient Management

Since the etiology of PAN is not known, careful attention to details of the history and work up are essential. For example in patients with documented antecedent streptococcal infection, the treatment of this infection and consideration of streptococcal prophylaxis in these patients with low dose pencillin should be made. In those patients taking hormonal therapy with CPAN, it should be held or stopped if possible to see if this may be of benefit.

Treatment should be aggressive enough to prevent ulcerations of the skin or to heal ulcerations to reduce pain and prevent secondary infection.